The incidence of cigarette smoking addiction in individuals with major depression is reported to be approximately 50%. That nicotine can be "protective" against depressive symptoms in this patient population and that nicotine may even have antidepressant effects in non-smoking depressed patients is suggestive of a complex interplay between nicotine and neurochemicals, responsible for regulation of mood. Nicotine has been shown to have effects on glutamate in the rodent cortex and gamma- aminobutryic acid (GABA)ergic and glutamatergic systems in rodent hippocampus. Using proton magnetic resonance spectroscopy (1H-MRS) our group has found a reduction in occipital cortex GABA levels in smoking and non-smoking patients with major depression compared to healthy smoking and non-smoking controls. In addition, depressed smokers had a 25% reduction in cortical GABA levels compared to depressed non-smokers. The overarching goal of this project is to further knowledge of the pathophysiology of nicotine addiction and nicotine's effects on negative effect by conducting 1H-MRS to measure cortical GABA, glutamate and glutamine pre and post 40 hours smoking abstinence in three groups; 1) depressed smokers, 2) non-depressed smokers with a history of major depression, and 3) healthy smoking controls. The pilot study outlined in this proposal will provide the first in vivo characterization of the impact of nicotine withdrawal on cortical amino acid neurotransmitters in humans. Findings from this investigation will serve to direct us in the development of a full-scale investigation in which we would include alcohol use as an additional focus, conduct 1H-MRS scans over a longer course of abstinence and match our subjects on a greater number of variables.